Project Summary Periodontitis is a prevalent inflammatory disease that causes destruction of the tooth-supporting tissues (periodontium). The maintenance of homeostatic mechanisms is essential for protection against inflammatory damage in the periodontium. In this context, the function of immune cells needs to be tailored according to specific environmental challenges; for instance, the ability to mount a robust immune response needs to be followed by timely resolution of inflammation and restoration of tissue integrity. This adaptation is known as functional immune plasticity and results from an intimate crosstalk of immune cells with tissue-derived factors, which, in turn, are regulated by and reflect changes of the tissue microenvironment. The functional characterization of a novel endogenous homeostatic molecule, derived from periodontal tissue-resident cells and designated developmental endothelial locus-1 (Del-1), has significantly contributed as a prototype paradigm to the emerging concept that tissues have a ?regulatory say? over the host immune response. This project investigates the overarching hypothesis that Del-1 acts as a local endogenous regulator of functional immune plasticity by not only regulating periodontal inflammation but also by promoting resolution thereof, and hence periodontal homeostasis. The proposal comprises three specific aims and focuses on relevant animal model-based mechanistic and intervention studies, including mice with lineage-specific deletions or overexpression of Del-1. In Aim 1, it is proposed that Del-1 promotes the resolution of periodontal inflammation. Aim 2 investigates the mechanism(s) by which Del-1 promotes homeostatic immunity. Specifically, it is proposed that Del-1 modulates macrophage plasticity via two complementary mechanisms; inhibition of inflammatory signaling and promotion of a pro-resolution reprogramming of macrophages, both of which may impact the function of other immune cells, such as T cells. Aim 3 is to determine the importance of the location of Del-1 expression in the regulation of periodontal inflammation and bone loss. The concept to establish here is that the cellular source and location of homeostatic molecule expression is functionally important in that it allows it to perform distinct functions in an appropriate context. This application therefore offers a fundamentally new insight into the local mechanisms that govern and tailor the function of the immune system. The proposed research is likely to reveal hitherto unknown mechanisms of immune system plasticity relevant to the pathogenesis of oral diseases; these mechanisms can be harnessed to develop innovative approaches to inhibit destructive inflammation and restore tissue integrity.